Cardiac output, or total blood flow to the periphery, is perhaps one of the most vital quantities to be able to monitor in a critically ill patient. A decrease in cardiac output may be one of the first indicators of a deterioration in circulatory function. Conversely, an increase in cardiac output may indicate the beneficial effect of a therapeutic intervention. The arterial blood pressure which is often monitored in intensive care unit patients provides a poor indication of cardiac output because of the body's extensive feedback system which can maintain arterial blood pressure in a narrow range despite wide variations in cardiac output.
There are currently a number of technologies for determining cardiac output: thermodilution, dye dilution, ultrasound and bioimpedance. Although these technologies can provide useful information, they have a number of shortcomings as discussed below.
At present thermodilution is the standard technique for measuring cardiac output in critically ill patients. Thermodilution measurements are conducted in the following manner. A catheter is advanced through a peripheral vein into the vena cava, through the right heart and into the pulmonary artery. A bolus of chilled fluid is then injected into the catheter and emerges from an upstream port in the catheter. The blood temperature is recorded at a downstream thermistor embedded in the catheter. Cardiac output is then determined from a numerical analysis of the time evolution of the blood temperature.
Thermodilution has several disadvantages:                (1) It requires the placement of a pulmonary artery catheter—this is a non-trivial invasive procedure and is not feasible in all patients, e.g. newborn infants. This procedure is also very expensive and time and personnel intensive.        (2) The measurement is not continuous in time—and generally is at most repeated every few hours.        (3) The measurement is not always accurate, especially in low blood flow conditions.        
Dye dilution techniques are sometimes used in the intensive care unit setting. This technique is also noncontinuous and personnel intensive. This technique requires venous injection of a dye and measurement of the dye dilution in a series of arterial blood samples drawn from an arterial catheter.
Similarly, oxygen consumption (Fick) methods are also used occasionally in the cardiac catheterization laboratory. This method involves simultaneous measurement of central venous and arterial oxygen content of blood and measurement of ventilatory oxygen uptake (oxygen consumption). This cumbersome method is regularly used only in the catheterization laboratory.
Ultrasound techniques for measuring cardiac output generally rely upon the measurement of the Doppler shift in the frequency of an ultrasound beam reflected from the flowing aortic blood. This technique suffers from the difficulty in stabilizing an external ultrasound transducer, the need to assume a cross-sectional flow profile of the blood in the aorta, and the uncertainty in the angle between the ultrasound beam and the aorta.
The Transonic Systems Flowmeter (Ithaca, N.Y.) utilizes an ultrasound transit-time principle to measure flow, but is not practical for routine clinical use, because it is highly invasive requiring the placement of a transducer directly around the aorta. Conventional electromagnetic flowmeters are also not practical for routine clinical use because they also require placement of a transducer directly around the aorta.
Bioimpedance techniques involve measuring changes in the electrical impedance of the thorax during the cardiac cycle. Bioimpedance changes are only indirectly related to changes in cardiac flow and are especially unreliable in patients with cardiovascular or respiratory illnesses in which the electrical impedance properties of the thorax are altered.
A continuous cardiac output monitor would be of great practical value in the management of intensive care unit patients, patients in the operating and recovery rooms, as well as patients undergoing cardiac catheterization. Such a device would provide the physician with immediate feedback on the outcome of different interventions such as varying infusion rates of cardioactive and vasoactive drugs, infusion rates of intravenous fluids, ventilator settings, etc.
It would be very advantageous to have a device which could monitor cardiac output by analyzing a systemic artery or pulmonary artery blood pressure signal, or other physiologic signal related to circulatory pressures or flows. It would be desirable for such a device to be able to compute a quantity proportional to stroke volume for each heart beat, a signal proportional to the phasic cardiac output flow signal (the phasic cardiac output signal is a signal with sufficient time resolution to reflect variations in flow within a single cardiac cycle), a signal proportional to the time-averaged cardiac output (the time-averaged cardiac output reflects the cardiac output averaged over several heart beats), and/or a quantity proportional to the current value of the vascular resistance. It would be desirable for such a device to be able to use as input the amplified arterial blood pressure signal from an existing bedside monitor. The blood pressure transducer used could be an arterial catheter placed in essentially any arterial vessel—in particular in the radial artery or other peripheral arteries. Peripheral arterial catheters are very often in place in intensive care unit patients, and placing a peripheral arterial line is a relatively simple procedure. This device optimally could also utilize as input the pulmonary artery pressure recorded from a pulmonary artery catheter. In addition, it would be desirable for such a device to be able to use as input other physiologic waveforms related to circulatory pressures or flows. These might include continuous noninvasive blood pressure monitor signals, measurements of the optical density or reflectance of peripheral tissue using photoelectric sensors and measurement of fluctuations in peripheral tissue pressures, etc.
Many investigators have attempted to analyze the arterial blood pressure waveform in order to compute beat-to-beat stroke volume (see for example, W. F. Hamilton and J. W. Remington, “The Measurement of Stroke Volume from the Pressure Pulse,” American Journal of Physiology, Volume 148, pp 14-24, 1947; J. A. Herd, N. R. LeClair and W. Simon, “Arterial Presure Pulse Contours during Hemmorrhage in Anesthetized Dogs,” J. Applied Physiology, Volume 21, pp 1864-1868,1966; T. K. Kouchokos, B. S. Sheppard and D. A. McDonald, “Estimation of Stroke Volume in the Dog by a Pulse Contour Method,” Circulation Research, Volume 26, pp 611-623, 1970; A. A. Schoenberg, U. Mennicken, R. Simon, P. Brambring and P. H. Heintzen, “Stroke Volume estimation for Aortic Pressure with Correction for Arrhythmias,” Journal of Cardiology, Volume 2, pp 55-65, 1974; H. R. Warner, H. J. C. Swan, D. C. Connolly, R. G. Tompkins, and E. H. Wood, “Quantitation of Beat-to-Beat Changes in Stroke Volume from the Aortic Pulse Contour in Man,” Journal of Applied Physiology, Volume 5, pp 495-507, 1953; K. H. Wesseling, N. T. Smith, W. W. Nicholis, B. de Wit and J. A. P Weber, “Beat-to-Beat Cardiac Output from Arterial Pressure Pulse Contour,” in Measurements in Anesthesia, Feldamn, Leight and Spierdijk, Eds, Leiden: Leiden Universary Press, 1974). These attempts were for the most part based on semi-empirical mathematical formulas, and failed to yield good correlation between stroke volume derived from analysis of the arterial pressure waveform and true stroke volume over a range of physiologic conditions. Bourgeois et al (M. J. Bourgeois, B. K. Gilbert, G. von Bernuth, and E. H. Wood, “Continuous Determination of Beat-to-Beat Stroke Volume from Aortic Pressure Pulses in the Dog”, Circulation Research, Volume 39, 1976, pp 15-24) did successfully demonstrate in animal studies that analysis of the aortic blood pressure waveform based on a parallel resistor-capacitor circuit of the peripheral circulation yielded could yield a quantity which varied linearly with the stroke volume measured using an electromagnetic flowmeter over a wide range of physiologic conditions.
However, the method of Bourgeois et al only worked when the diastolic decay of the aortic blood pressure waveform was described by a perfect exponential function. In the animal studies this was accomplished by varying the position of the aortic blood pressure monitoring catheter until a location was found in the central aorta where the decay was indeed exponential. Clinically, because of the risk of blood clot formation and embolization it is not practical to leave an aortic catheter in place. Arterial pressure is generally measured using a peripheral arterial recording—usually in the radial artery. The arterial blood pressure waveform is distorted as it propagates through the arterial tree and the diastolic decay is generally very non-exponential by the time it reaches peripheral arteries. The method of Bourgeois fails when a peripheral arterial trace is used as input, thus rendering the technique useless from a clinical point of view. Moreover, the method of Bourgeois suffers from several other defects. The method of Bourgeois provides a measure proportional to stroke volume for each beat but does not provide the actual phasic cardiac output signal. The waveform of the phasic cardiac output signal could provide important information regarding cardiac contractility. Finally, the method of Bourgeois et al is dependent on the accurate determination of the end of systole for each beat. Bourgeois et al attempted to accomplish this determination by analysis of the dicrotic notch of the central aortic waveform. This method for the determination of the end of systole may be inaccurate, particularly for peripheral arterial pressure traces where the dicrotic notch may be shifted, distorted or absent.
Welkowitz et al (W. Welkowitz, Q. Cui, Y. Qi, and J. B. Kostis, “Noninvasive Estimation of Cardiac Output”, IEEE Transactions in Biomedical Engineering, Volume 38, pp. 1100-1105, 1991) utilized an adaptive aorta model in conjunction with carotid and femoral measurements to estimate cardiac output. This method suffers from a number of defects. It requires two simultaneous pressure measurements. At one of the sites (carotid artery) one cannot safely place a catheter, rendering continuous monitoring of arterial pressure and thus cardiac output impossible; the second site (femoral artery) also is not suitable for leaving an arterial catheter in place for prolonged periods or otherwise continuously measuring arterial pressure at this site. The adaptive aortic model contains a very specific model and limited model of the circulation which is not physiologically accurate, with multiple parameters which cannot be adequately fit with experimental data (see for example, A. Cappello and A. Cardaioli, ‘Comments on “Noninvasive Estimation of Cardiac Output”, IEEE Transactions on Biomedical Engineering, Volume 40, 1993, pp 504-505).
More recently a method for measuring cardiac output has been developed by measuring the impulse response function between cardiac contractions and the arterial blood pressure waveform (Mukkamala R, Kuiper J, Ahmad S, Lu Z. Cardiac output monitoring in intensive care patients by radial artery pressure waveform analysis. Conf Proc IEEE Eng Med Biol Soc. 2004; 5:3712-3715; Swamy G, Ling Q, Li T, Mukkamala R. Blind identification of the aortic pressure waveform from multiple peripheral artery pressure waveforms. Am J Physiol Heart Circ Physiol. 2007; 292(5):H2257-2264; Lu Z, Mukkamala R. Continuous cardiac output monitoring in humans by invasive and noninvasive peripheral blood pressure waveform analysis. J Appl Physiol. 2006; 101(2):598-608; Mukkamala R, Reisner A T, Hojman H M, Mark R G, Cohen R J. Continuous cardiac output monitoring by peripheral blood pressure waveform analysis. IEEE Trans Biomed Eng. 2006; 53(3):459-467; Mukkamala R, Kim J K, Li Y, Sala-Mercado J, Hammond R L, Scislo T J, O'Leary D S. Estimation of arterial and cardiopulmonary total peripheral resistance baroreflex gain values: validation by chronic arterial baroreceptor denervation. Am J Physiol Heart Circ Physiol. 2006; 290(5):H1830-1836; United States Patent Application 20040158163 Methods and apparatus for determining cardiac output; United States Patent Application 20070197921 Methods and apparatus for determining cardiac output and left atrial pressure). However, this method does not provide a continuous signal proportional to cardiac output nor does it provide a means for estimating stroke volume on a beat-to-beat basis.
What is needed is a reliable accurate means of measuring a stroke volume, phasic cardiac output, time-averaged cardiac output and vascular resistance from systemic arterial pressure traces, pulmonary artery traces or other physiologic signals.